1. Field of the Invention
The present invention discusses increased recovery of intermediates which are useful for the preparation of sex hormones.
2. Discussion of the Art
It has long been known that many sex hormones may be prepared chemically through a variety of oxidation and reduction reactions. For instance, in an article entitled "Progesterone from 3-acetoxybisnor-5-cholenaldehyde and 3-ketobisnor-4-cholenaldehyde" by Heyl et al, June 1950, JACS; pp. 2617-2619, the aforementioned compounds are described as useful in the production of progesterone.
Basically the Heyl et al article, supra, discloses that the named subject compounds may be treated with acetic anhydride using sodium acetate as a catalyst to form the corresponding bisenol acetate and the 21 enol acetate. These compounds are then treated as discussed in the reference through chemical conversion to give progesterone.
In particular, one aspect of the Heyl et al reference discloses that by using stigmasterol as a starting material in an Oppenauer oxidation stigmastadienone is obtained. Through ozonolysis of the stigmastadienone a relatively high yield of 3-ketobisnor-4-cholenaldehyde may be obtained. The 3-ketobisnor-4-cholenaldehyde is then converted to the enol acetate and bisenol acetate through heating at reflux under nitrogen for six hours in a mixture of acetic anhydride and sodium acetate. The product of the acetic anhydride treatment which is described as a slightly yellow residue, is then dissolved in chloroform. Through this process the insoluble sodium acetate remaining in the reaction mixture may be filtered off and washed with additional chloroform to increase the recovery of the enol acetate and bisenol acetate products.
Both enol acetates are then described as being subjected to ozonolysis, followed by vacuum removal of the solvent. This residue comprising the ozonized product is then taken up in acetic acid and ether followed by mixing with zinc dust. This mixture is then stated as having been diluted with ether, filtered, and the ether solution washed with a sodium hydroxide solution, water and dried. The ether is then evaporated and the residue is refluxed with a mixture of methanol and sulfuric acid to hydrolize any C-3 enol ester which may be present in the ozonized mixture. The Heyl et al reference then goes on further to state that this latter solution may be concentrated by vacuum to half its volume and extracted with ether. The ether solution is then stated to be washed with sodium hydroxide, water and dried over sodium sulfate. Progesterone is stated to be obtained by taking the dried residue up in anhydrous ether through warming and then allowing the prisms of progesterone to separate on standing. The over-all yield of progesterone is stated to be 60%.
It has now been found that through following the process described in the Heyl et al reference, that a by-product is obtained which diminishes the potential yield of progesterone. Moreover, the by-products are extremely difficult to separate from progesterone due to the similar structure. The by-products are a mixture of 6-alpha and 6-beta hydroxy progesterones. The production of these 6-hydroxy progesterone compounds has been found to be proportional to the amount of bisenol acetate present in the mixture of enol acetate and bisenol acetate.
It is, therefore, desirable to minimize the amount of the bisenol acetate which is present with the enol acetate in order to greatly increase the amount of progesterone formation upon subsequent processing.
Throughout the specification and claims percentages and ratios are given by weight and temperatures are in degrees Celsius, unless otherwise indicated.
The use of the terms enol acetate and bisenol acetate herein correspond to 3-oxo-20-methylpregna-4,20(21)-diene-21-yl-acetate and 20-methylpregna-3,5,20(21)-triene-3,21-diol-diacetate respectively. It is also noted that 3-ketobisnor-4-cholenaldehyde referred to in Heyl et al is also known as 3-keto-4-pregnene-20-carboxaldehyde.